Diseases of the neural retina or retinal pigment epithelium (RPE) cause a substantial number of sight-impairing disorders, many of which lead to the degeneration and death of photoreceptor cells. A number of naturally occurring inherited retinal degeneration (RD) diseases have been identified that are true homologues of human diseases. Our research team has been instrumental in demonstrating that AAV-mediated gene therapy for the retina in disease models plays a critical role in the translational continuum by permitting a rapid, cost-effective, and clinically relevant assessment of therapeutic responses and long-term outcomes of retinal gene therapy. However, the success of prior gene therapy trials depended on the presence of viable, albeit diseased, target cells. In contrast, the substantial loss of target cells in advanced RD will require therapeutic strategies that permit regeneration or replacement of photoreceptor cells and restoration of neural connectivity. Models of human retinal diseases can provide the foundational knowledge needed for photoreceptor replacement therapies to improve visual function, as specified in the AGI RFA. We have assembled a team of investigators with expertise in neural progenitor and pluripotent stem cell biology, retinal cell differentiation, inherited retinal disease pathology and therapy, and functional analysis of experimental RD treatments. The investigators have the expertise to assess therapeutic responses and to develop appropriate outcome measures to evaluate safety and efficacy. We have a dedicated retinal disease research facility to assess models of human retinal disorders. Our goal is to develop models in which to investigate the replacement of photoreceptors under disease conditions. The models will be used to identify key parameters of cell transplantation, engraftment, and differentiation that will be critical for studies of disease-specific applications of regenerative medicine for the retina. Key properties to be studied are physical transplantation parameters, distribution of donor cells within the host retina, donor cell differentiation and survival, cell connectivity and functionality within the retina, connectivity to the visual pathways in the brain and CNS processing, and behavioral assays for vision. Transplantation parameters will be studied using xenografts derived from two well-characterized and readily available human pluripotent stem cell reporter lines that label cones and rods or only rods. Concurrently, we will develop a within-species system for photoreceptor replacement by producing equivalent iPSCs and cone/rod and rod-only iPSC reporter lines for replacement of retinal photoreceptor cells to recapitulate the engraftment that would occur in human clinical trials using human cells. Once developed, the photoreceptor precursor cell transplants will be analyzed for integration and functionality in disease models in which differentiation into new rod and cone visual cells can be evaluated.